In all vertebrate animals studied, the homeostasis of adult blood and immune cells is ultimately maintained by rare subsets of hematopoietic stem cells (HSCs). During a brief window during embryonic development, these HSCs arise de novo from hemogenic endothelium comprising the floor of the dorsal aorta (DA) in a process that appears to be conserved amongst all vertebrates. A more complete understanding of the signaling pathways that instruct HSC emergence could in principle inform in vitro approaches utilizing pluripotent precursors to create patient-specific HSCs. This would enable autologous transplantation strategies to combat a multitude of disorders including hematopoietic neoplasms, solid cancers, immune deficiencies, and anemia without the currently common complications of immune rejection or graft-versus-host disease. Despite decades of efforts, this goal has not yet been achieved, in part due to an incomplete understanding of the native molecular cues needed to establish HSC fate. The signaling events underlying the developmental specification of hemogenic endothelium remain poorly understood. We recently made the surprising discovery that proinflammatory signaling, in the absence of infection, is required for proper HSC emergence. These findings led us to study the Progranulin factors, which serve to regulate the inflammatory response in other settings. Our preliminary data indicate that the Progranulin-a protein is required for normal HSC development. Interestingly, during this temporal window Pgrna is expressed only by macrophages. Our preliminary data suggest that a specific macrophage subset derived from the erythromyeloid progenitor expresses Pgrna. These findings suggest that a specific population of macrophages is required for the normal development of HSCs through the function of Pgrna. These are novel findings indicating that the lineal ontogeny of macrophages dictates specific functions, and will better inform us as to how the embryo generates HSC fate. !

Public Health Relevance

Hematopoietic stem cells (HSCs) are rare cells within human bone marrow that are responsible both for the life-long replenishment of all blood cell lineages and for the curative effects of bone marrow transplantation. The creation of human induced pluripotent cells holds great promise for cellular regeneration therapies, but we cannot currently instruct these cells to specifically generate HSCs in vitro. The overall goal of this application is to determine how macrophages, via their production of Progranulin-a, instruct HSC formation in the vertebrate embryo, with the ultimate goal of replicating HSC generation in vitro for clinical utility.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Development - 1 Study Section (DEV1)
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Singleton, Kentner L
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University of California, San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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